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Effect and Safety of Local Injection of Botulinum Toxin Type B Against Digital Ulcer in Systemic Sclerosis

Primary Purpose

Systemic Sclerosis Patients With Digital Ulcers

Status

Completed

Phase

Phase 2

Locations

Japan

Study Type

Interventional

Intervention

Botulinum toxin type B (2500 units / vial)

Physiological saline

About this trial

This is an interventional treatment trial for Systemic Sclerosis Patients With Digital Ulcers focused on measuring Systemic aclerosis, digital ulcer, botulinum toxin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients diagnosed with SSc in diagnostic criteria (Appendix 1) by the American-European Rheumatology Association
Patients who have Raynaud's phenomenon from consultation, inquiries, etc. judged by Clinical responsibility (sharing) doctor
Patients with digital ulcer at acquiring consent The criteria for digital ulcers are as follows.
- It is a peripheral ulcer from the proximal interphalangeal joint and the thumb interphalangeal joint (including the interphalangeal joint).
- The continuity of coating by the epithelium has been lost and there is a depth that is visible to the eye. Incidentally, when exposed, cases covered with eschar or necrotic tissue are also included.
- If the exposure is not clearly recognized (crusted or covered with necrotic tissue), the investigational responsibility (shared) doctor can judge that the epidermis and the dermis are missing.
- It should not be the paronychia、crack、digital pitting scars.
- It should not be attached to the projection of the calcification.
- Size: The maximum diameter (major axis) is 0.5 cm or more.
- Bones, tendons and joints are not exposed.
- It is not accompanied by obvious infection findings.
At the time of acquiring consent Patients over 18 years old
Patients for whom consent has been obtained in writing on participation of this trial

Exclusion Criteria:

Patients with Raynaud's phenomenon due to diseases other than SSc
Patients with systemic neuromuscular junction disorder (myasthenia gravis, Lambert-Eaton syndrome, amyotrophic lateral sclerosis etc.)
Patients with advanced respiratory dysfunction
Patients with a history of hypersensitivity to components of botulinum toxin type B (botulinum toxin type B, human serum albumin, succinate buffer) or other botulinum toxin
Patients who received botulinum toxin formulation within 4 months before study drug administration or who have continued efficacy of botulinum toxin at the time of administration of investigational drug even when administered more than 4 months ago
Patients who received endothelin receptor antagonist within 60 days before study drug administration
Patients who received the following medications within 14 days prior to study drug administration
- Argatroban hydrate injection
- Prostaglandin E1 Injection (eg alprostadil injection)

Sites / Locations

Gunma University Graduate school of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Botulinum toxin group

Physiological saline (control drug) group

Arm Description

400 units in one injection site（0.2mL） Total 2000 units（1.0mL）（For both hands total 4000 units; 2.0 mL）

0.2mL in one injection site Total 1.0mL (For both hands total 2.0 mL)

Outcomes

Primary Outcome Measures

Percentage of subjects who completely lost index ulcer 8 weeks after administration

The primary end point was the percentage of subjects with complete disappearance of index ulcer 8 weeks after administration. The index ulcer was defined as the largest DUs in the hand. The size of DU was measured as both the longest diameter of the ulcer and the diameter perpendicular to the center of the ulcer's diameter. Complete disappearance is defined as the disappearance of the area of the ulcer that has become epithelialized and covered by the epidermis from the periphery of the ulcer and continued coverage of the ulcer surface area that has been restored.

Secondary Outcome Measures

the percentage of subjects with complete disappearance of index ulcer at 4, 12, and 16 weeks after administration

the rate of change in the number of DUs per hand

the number of newly formed DUs

the number of newly formed DUs per hand

the changes in RP severity were assessed using Raynaud's Condition Score [RCS]

the changes in RP severity were assessed using Raynaud's Condition Score [RCS]. RCS is a daily self-assessment of RP activity using a 0-10 ordinal scale. RCS incorporates the cumulative daily frequency, duration, severity, and effect of RP attacks. RCS was averaged over a 7-day period preceding the baseline and each subsequent visit.

the changes of investigator rating Raynaud's Condition Score [RCS]

the changes of investigator rating Raynaud's Condition Score [RCS]. Investigator rating RCS was also assessed by the investigator (SM).

the changes in the score of pain/numbness severity assessed using the 100-mm Visual Analog Scale (VAS)

Pain/numbness severity was assessed using the 100-mm Visual Analog Scale (VAS). Pain/numbness severity was assessed using the 100-mm Visual Analog Scale (VAS) (range 0-100; 0 refers to no pain/numbness, and 100 refers to worst imaginable pain/numbness)

the changes of the recovery of skin temperature in the finger with the index ulcer

the skin temperature of the finger was measured just after and 10 minutes after an ice-bath immersion

the changes in the attack duration of Raynaud's phenomenon

the changes in the number of attacks of Raynaud's phenomenon per day

the number of attacks of Raynaud's phenomenon per day was assessed for 7days

Full Information

NCT ID

NCT03007004

First Posted

December 28, 2016

Last Updated

May 12, 2020

Sponsor

Gunma University

1. Study Identification

Unique Protocol Identification Number

NCT03007004

Brief Title

Effect and Safety of Local Injection of Botulinum Toxin Type B Against Digital Ulcer in Systemic Sclerosis

Official Title

Trial to Confirm the Effect and Safety of Local Injection of Botulinum Toxin Type B Against Digital Ulcer in Systemic Sclerosis

Study Type

Interventional

2. Study Status

Record Verification Date

May 2020

Overall Recruitment Status

Completed

Study Start Date

December 12, 2016 (Actual)

Primary Completion Date

May 14, 2019 (Actual)

Study Completion Date

May 14, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Gunma University

4. Oversight

5. Study Description

Brief Summary

Efficacy and safety of local infusion of botulinum toxin type B in patients with systemic sclerosis (SSc) with digital ulcer is evaluated by a randomized, double-blind study.

Detailed Description

To assess the efficacy and safety of local injection of botulinum toxin type B (BTX-B) against digital ulcers (DUs) and Raynaud's phenomenon (RP) in patients with systemic sclerosis (SSc). In a randomized, double-blind, placebo-controlled, investigator-initiated clinical trial (phase II), 10 patients with SSc and RP-related DUs were randomly and evenly assigned to a placebo control group or treatment group taking BTX-B injections. The degree of improvement in DU, change in size, number of new DUs, improvement in symptoms of RP, and adverse events were recorded.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Systemic Sclerosis Patients With Digital Ulcers

Keywords

Systemic aclerosis, digital ulcer, botulinum toxin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Botulinum toxin group

Arm Type

Experimental

Arm Description

400 units in one injection site（0.2mL） Total 2000 units（1.0mL）（For both hands total 4000 units; 2.0 mL）

Arm Title

Physiological saline (control drug) group

Arm Type

Sham Comparator

Arm Description

0.2mL in one injection site Total 1.0mL (For both hands total 2.0 mL)

Intervention Type

Drug

Intervention Name(s)

Botulinum toxin type B (2500 units / vial)

Other Intervention Name(s)

BTX-B (E2014, Eisai, NerBloc®)

Intervention Description

BTX-B (E2014, Eisai, NerBloc®) was injected subcutaneously from the palmar side into seven locations around interphalangeal metacarpophalangeal joints, targeting the neurovascular bundles just proximal to the A1 pulley (the radial and ulnar sides of the first finger, the radial side of second finger, the ulnar side of the fifth finger and between the second to fifth fingers). Three locations between the second and third fingers, the third and fourth fingers, and the fourth and fifth fingers were injected with 400 U (0.2 ml) of BTX-B. In addition, the radial and ulnar sides of the first finger, the radial side of the second finger, and the ulnar side of the fifth finger were injected with half a dose of BTX-B (200 units; 0.1 ml). A total of 2000 U (1.0 ml) of BTX-B was injected into one hand. Injections were performed using a 30-gauge needle.

Intervention Type

Drug

Intervention Name(s)

Physiological saline

Intervention Description

Saline solution was injected subcutaneously from the palmar side into seven locations around interphalangeal metacarpophalangeal joints, targeting the neurovascular bundles just proximal to the A1 pulley (the radial and ulnar sides of the first finger, the radial side of second finger, the ulnar side of the fifth finger and between the second to fifth fingers). Three locations between the second and third fingers, the third and fourth fingers, and the fourth and fifth fingers were injected with saline (0.2 ml). In addition, the radial and ulnar sides of the first finger, the radial side of the second finger, and the ulnar side of the fifth finger were injected with half a dose of saline (0.1 ml). A total of 1.0 ml of saline was injected into one hand. Injections were performed using a 30-gauge needle.

Primary Outcome Measure Information:

Title

Percentage of subjects who completely lost index ulcer 8 weeks after administration

Description

Time Frame

8 weeks after administration

Secondary Outcome Measure Information:

Title

the percentage of subjects with complete disappearance of index ulcer at 4, 12, and 16 weeks after administration

Description

the percentage of subjects with complete disappearance of index ulcer at 4, 12, and 16 weeks after administration

Time Frame

at 4, 12, and 16 weeks after administration

Title

the rate of change in the number of DUs per hand

Description

the rate of change in the number of DUs per hand

Time Frame